Nitrofuryl-alpha-halo-hydrazones

ABSTRACT

5-Amino-4-cyano-3-(5-nitro-2-furyl)-pyrazoles, substituted in 1position of the pyrazole moiety by alkyl, hydroxyalkyl or carbalkoxy, and pharmaceutically acceptable acid addition salts thereof, have antimicrobial properties; compositions containing these compounds and methods for the treatment of microbial infections and protecting organic material against microbial attack; a typical embodiment is 5-amino-4-cyano-1-methyl-3-(5nitro-2-furyl)-pyrazole.

United States Patent [191 Howarth et al.

v 111 3,835,165 [451 Sept. 10,1974

[ NITROFURYL-ALPHA-HALO- HYDRAZONES [7 5] Inventors: Graham Arton Howarth, Wilmslow;

William Hoyle, Bramhall, both of England [73] Assignee: Ciba-Geigy Corporation, Ardsley,

[22] Filed: June 15, 1972 [21] Appl. No.2 263,047

Related US. Application Data [62] Division of Ser. No. 15,209, Feb. 27, 1970, Pat. No.

[52] US. Cl. 260/347.5, 260/347.7 [51] Int. Cl C07d 5/30 [58] Field of Search 260/347.7, 347.5

[56] References Cited UNITED STATES PATENTS 3,245,999 4/1966 Haack et al 260/347.7

Pn'mary Examiner-Henry R. Jiles Assistant Examiner-Bernard Dentz Attorney, Agent, or Firm-Joseph G. Kolodny [5 7] ABSTRACT 5-Amino-4-cyano-3-( 5-nitro-2-furyl )-pyrazoles, substi- 4 Claims, No Drawings 1 NITROFURYL-ALPHA-HALO-HYDRAZONES This is a division of application Ser. No. 15,209 filed Feb. 27, 1970 now US. Patent 3,682,953.

DETAILED DESCRIPTION microbial infections in mammals and to methods of protecting organic material against microbial attack.

More particularly, the present invention pertains to compounds of formula wherein R is unsubstituted or hydroxy-substituted alkyl having from one to five carbon atoms, or carbalkoxy having from one to five carbon atoms in the alkyl moiety; as well as to pharmaceutically acceptable acid addition salts thereof.

The alkyl moiety constituting or forming part of the group R, contains from one to five carbon atoms, but is preferably a straightor branched-chain radical containing from one to three carbon atoms. Examples of alkyl moieties include the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl and n -pentyl groups. If R represents a carbalkoxy group, then it is preferred that it should be an ethoxycarbonyl group.

The present invention also provides salts of nitrofuryl-pyrazoles of formula I with organic and inorganic acids. Examples of such acids are hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulphonic, ethandisulphonic, acetic, trichloro-acetic, oxalic, succinic, maleic, fumaric, malic, tartaric, citric and mandelic acids.

The compounds of the present invention are prepared by reacting the corresponding nitrofurylnitrilimine, which in one of its canonical forms may be represented by the formula II,

N HR (III) wherein X represents a halogen atom, with a base. This process may, if desired, be effected in the presence of a further conventional hydrogen halide acceptor. The halogen present in the halohydrazone of formula III is preferably chlorine or bromine.

The nitrofuryl-oz-halo-hydrazones of formula III are new compounds. They are produced, for example, by reacting the corresponding nitrofuryl-hydrazones having the formula IV,

with an N-halo compound bearing the requisite halogen.

The present invention also provides a modification of the process for producing a nitrofuryl-pyrazole of formula I, which comprises reacting the corresponding nitrofuryl-hydrazone of formula IV with an N-halo compound and treating the reaction mixture thus obtained with malononitrile in the presence of a base. ln'tl'iis process of the invention, the intermediate product from the reaction of the nitrofuryl-hydrazone of formula IV with the N-halo compound, is not isolated before contacting with the malononitrile.

Examples of N-halo compounds which may be used in both these processes are N-halo benzotriazonles and N-halo succinimides. Of the N-halo suecinimides, the N-chloro compound may be used, but the N-bromo derivative is preferred.

The compounds of the invention having formula I, have valuable antimicrobial properties, and in particular having antibacterial, anthelminthic, antiprotozoal, coccidiostatic, trypanocidal and antimalarial activity of value in human or veterinary medicine. The compounds are particularly valuable in the treatment of infections of the intestinal and urinary tracts. The compounds may also be used to protect a high molecular weight hydrophobic or other organic material susceptible to bacterial or other microbial deterioration by contacting, impregnating or otherwise treating the organic material with the compounds in amounts up to about 5 percent by weight. The compounds also find application as growth-promoting additives to animal feedstuffs, to'which they may be added in proportions of from 5 to 500 parts per million.

The antimicrobial activity of the compounds of formula I can be demonstrated in avariety of in vitro and in vivo tests. In standard in vitro test, for example 5- amino-4cyanol -methyl-3-( 5-nitro-2-furyl )-pyrazole and 5-amino-4-cyanol 2-hydroxyethyl )-3-( 5-nitro-2- furyI)-pyrazole, have an excellent inhibiting activity on the growth of Staphylococcus, Escherichia coli, Klebsiella, Salmonella, Candida alb. and other bacteria.

As an example of the in vivo use of the compounds of formula I, the use of 5 -amino-4-cyano-1-( 2- hydroxyethyl)-3-(5-nitro-2-furyl)-pyrazole in mice infected with Staphylococcus aureus, may be described. Groups of five albino mice are infected by intraperitoneal injection of 0.2 ml of a suspension of pathogenic gen'ns which causes a mortality rate of percent in a group of untreated control mice. The test compound is administered per os by means of a stomach tube, twice on the day of infection. The duration of the therapy is adapted to the virulence of the pathogenic germ.

The mice are now observed and the surviving mice are counted on the fourth day. For each dose of the test compound, the cumulative mortality is then calculated according to the method of L. J. Reed and M. Muench, Am.J.I-Iyg. 27, 493 (1938). From the different mortality rates, the curative dosage necessary for the survival of 50 percent of the test animals, the CD is calculated by the same method of Reed and Muench. The CD thus determined is found to be far below the toxic dose, and indicates that 5-amino-4-cyanol 2- hydroxyethyl)-3(5-nitro-2-furyl)-pyrazole has an excellent activity against Staphylococcus aureus.

For their intended internal use in mammals, the compounds of formula I are administered orally in daily dosages of from about 1 to about 50 mg/kg, although the exact dosage has to be adjusted to the type of infection, the age, weight and the particular condition of the host being treated.

The compounds of formula I are administered advantageously in form of pharmaceutical compositions comprising an antimicrobially effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.

The type of carrier actually used depends to a great extent on the intended application; for external use, for example in disinfecting healthy skin, disinfecting wounds and in treating dermatoses and infections'of the mocus membranes caused by bacteria, ointments, powders and tinctures are used in particular. The ointment bases may be anhydrous, for instance they can consist of mixtures of wool fat and soft paraffin, or they can consist of aqueous emulsions in which the active substance is suspended. Suitable carriers for powders are, for instance, rice starch and other starches; the

bulk weight of the carriers may be lighter, if desired, for example by adding highly dispersed silicic acid, or may be made heavier by adding talcum. The tinctures may contain at least one active ingredient of the formula I in aqueous ethanol, in particular 45 percent to 75 percent ethanol, to which to percent of glycerol may be added, if desired. Solutions prepared from polyethylene glycol and other conventional solubility promoters, and also, optionally, from emulsifying agents, may be used with particular advantage in disinfecting healthy skin. The content of active ingredient in pharmaceutical compositions for external application is preferably in the range of from 0.1 to 5 percent.

Gargles or concentrates for their preparation, and tablets for slow dissolution in the mouth, are suitable for the disinfection of the mouth and throat. The former are preferably prepared from alcoholic solutions containing 1 percent to 5 percent of active substance to which glycerol or flavourings may be added. Lozenges, that is solid dosage units, preferably have a relatively high content of sugar or similar substances and a relatively low content of active substance, for instance 0.2 to 20 percent by weight, as well as the usual conventional additives such as binding agents and flavourings.

Solid dosage units, in particular tablets, dragees (sugar coated tablets) and capsules, are convenient for use in intestinal disinfection and for the oral treatment of urinary tract infections. These units preferably contain from 10 to percent of the compound formula I, to enable the administration of daily doses of from 0.1 to 2.5 grams to adults, or of suitably reduced doses to children. Tablets and dragee cores are produced by combining the compounds of formula I with solid, pul verulent carriers such as lactose, saccharose, sorbitol, maize starch, potato starch or amylopectin, cellulose derivatives or gelatines, preferably with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weight. Dragee cores may then be coated, for example with concentrated sugar solutions which can also contain gum arabic, talcum and/or titanium dioxide, or they may be coated with a lacquer dissolved in volatile organic solvents or mixture of solvents. Dyestuffs can be added to these coatings, for instance to differentiate between varying dosages. Soft gelatine capsules and other closed capsules consist, for example, of a mixture of gelatines and glycerol, and may contain, for example, mixtures of the compound of formula I with polyethylene glycol. Hard gelatine capsules contain, for example, granulates of an active substance with solid pulverulent carriers, for instance lactose, saccharose, sorbitol, mannitol, starches (such as potato starch, maize starch or amylopectin), cellulose derivatives of gelatines, and magnesium stearate or stearic acid.

In all forms for administration, a compound of formula I can be presentas sole active ingredient, or it may also be combined with other known pharmacologically active, especially antibacterially and/or antimycotically or otherwise antimicrobially active substances, for example to broaden the range of application. They can be combined for example, with 5,7- dichlor02-methyl-8-quinolin0l or other derivatives of 8-quinolinol, with sulfamerazine or sulfafurazole or other derivatives of sulfanilamide, with chloramphenicol or tetracycline or other antibiotics, with 3,4,-5- tribromosalicylanilide or other halogenated salicylanilides, with halogenated carbanilides, with halogenated benzoxazoles or benzoxazolones, with polychlorohydroxy-diphenylmethanes, with halogen-dihydroxydiphenyl sulphides, with 4,4-dichloro-2-hydroxydiphenylether or 2,4,4'-trichloro-2-hydroxydiphenylether or other polyhalogenhydroxydiphenylethers, or with bactericidal quarternary compounds or with certain dithiocarbamic acid derivatives such as tetramethylthiuram disulphide. Also, carriers, which themselves have favourable pharmacological properties may be used, for instance sulphur as a power base or zinc stearate as a compound of ointment bases.

The invention also provides a method of protecting an organic material susceptible to bacterial or other microbial attack which comprises treating the material with a nitrofuryl-pyrazole of formula I. The organic material may be, for instance a natural or synthetic polymeric material, a proteinaceous or carbohydrate substance, or a natural or synthetic fibre or textile material formed therefrom.

The invention also provides an animal feedstuff composition comprising a nitrofuryl-pyrazole of formula I in an amount sufficient to promote the growth of the animal fed with the composition.

The following examples will serve to further typify the nature of the present invention, but they should not EXAMPLE 1 a. To a mixture of 13.1 grams of 5-nitro-2- furaldehyde-a-chloro-N-ethoxycarbonyl-hydrazone and 3.3 grams of malononitrile dissolved in 75 millilitres of methanol is added slowly a mixture of 5.1 grams of triethylamine and 50 millilitres of methanol at 10C.

After allowing to stand, the crystalline precipitate is collected, washed with water and dried, and is then recrystallized from ethyl acetate.

The product is 5-amino-4-cyano-l-ethoxycarbonyl- 3-(5-nitro-2-furyl)-pyrazole having melting point 207C.

b. To a stirred mixture of 22.7 grams of 5-nitro-2- furaldehyde N-ethoxycarbonyl-hydrazone and 100 millilitres of concentrated hydrochloric acid and 20 millilitres of water is added slowly a solution of 14.2 grams of chlorine dissolved in 100 millilitres of glacial acetic acid at C. to 10C.

After further stirring, the mixture is diluted with 1 litre of water and the precipitate is collected, washed with water and dried. The dried solid is recrystallized from toluene.

The product is S-nitro-furaldehyde a-chloro-N- ethoxycarbonylhydrazone having melting point 125C.

, XAMW Z To a stirred solution of 33.8 grams of -nitro-2- lilitres of dimethylformamide are slowly added 35.8 grams of N-bromosuccinimide at 20C to 30C.

After further stirring, the mixture is diluted with 250 millilitres of iced water and the precipitate is collected, washed with water and dried. The dried solid is recrystallized from cyclohexane.

The product is 5-nitro-2-furaldehyde a-bromo-N- methylhydrazone having melting point 122C.

E AMPLE? W To a stirred solution of 16.9 grams of 5-nitro-2- furaldehyde N -methylhydrazone dissolved in 100 millilitres of dimethylformamide are slowly added 17.8 grams of N-bromosuccinimide at 2030C.

After further stirring, the mixture is cooled to C. To the stirred mixture is then added 6.6 grams of malononitrile followed by the slow addition of a mixture of 10.1 grams of triethylamine and 25 millilitres of dimethylformamide at 1020C.

After further stirring, the mixture is diluted with 500 millilitres of iced water and theprecipitate is collected, washed with water and dried. The dried solid is recrystallized from ethyl acetate.

The product is 5-amino-4-cyano-l-methyl-3-(5- nitro-2-furyl)-pyrazole having melting point 250C with decomposition.

EXAMPLE 4 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N'-isopropylhydrazone as starting material instead of 5-nitro-2-furaldehyde N methylhydrazone, the reaction conditions being the same.

The product is 5-amino-4-cyano-l-isopropyl-3-(5- nitro-2-furyl)-pyrazole.

EXAMPLE 5 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N-n-pentylhydrazone as starting material instead of 5-nitro-2-furaldehyde N- methylhydrazone, thereaction conditions being the same.

The product is 5-arnino-4-cyano-l-(n-pentyl)-3-(5- nitro-2-furyl )-pyrazole.

EXAMPLE 6 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N'-(2-hydroxyethyl).- hydrazone as starting material instead of 5-nitro-2- furaldehyde N-methylhydrazone, the reaction conditions being the same.

The product is 5-amino-4-cyano-l-(2-hydroxyethyl)-3-(5-nitro-2-furyl)-pyrazole, having melting point 216C.

EXAMPLE 7 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N-ethylhydrazone as starting material instead of 5-nitro-2-furaldehyde N'- methylhydrazone, the reaction conditions being the same.

The product is 5-amino-4cyano-l-ethyl-3-(5-nitro- 2-furyl)-pyrazole, having melting point 189C.

EXAMPLE 8 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N-n-propylhydrazone as starting material instead of 5-nitro-2-furaldehyde N- methylhydrazone, the reaction conditions being the same.

The product is 5-amino-4-cyano-3-( 5-nitro-2-furyl)- l-n-propyl-pyrazole, having melting point C.

EXAMPLE 9 The procedure described in Example 3 is carried out using 5-nitro-2-furaldehyde N-n-pentoxycarbonylhydrazone as starting material instead of 5-nitro-2- furaldehyde N'-methylhydrazone, the reaction conditions being the same.

The product is 5-amino-4-cyano-3-(5-nitro-2-furyl)- 1 -n-pentoxycarbonyl-pyrazole.

EXAMPLE 10 The procedure described in Example 2 is repeated using 5-nitro-2-furaldehyde N-(2-hydroxyethyl) hydrazone as starting material in place of 5-nitro-2- furaldehyde N'-methyl hydrazone, the reaction conditions being the same.

The product is 5-nitro-2-furaldehyde a-bromo-N'-( 2- hydroxyethyl) hydrazone having melting point 98C.

EXAMPLE 11 Preparation of Tablets:

EXAMPLE 12 Preparation of Dragees:

Composition: for 1.000 dragees: l

5-Amino-4-cyano- 1 methyl-3-(5-nitro-2- furyl)-pyrazole Maize starch Gelatin Glycerol Distilled water q.s. ad 100 ml Maize starch Talcum magnesium stearate Ill White Shelia Sugar Talcum Gum arabic Colloidal silicon dioxide Titanium dioxide dragee coating c 4O .....152%,I LL J ,L ...v ..w t

Preparation of a Syrup: Composition: for 1 liter:

5-Amino-4-cyano-l Z-hydroxyethyl 3-(5-nitro-2-furyl)-pyrazole l00.0 g Colloidal silicon dioxide 13.0 g p-Hydroxybenzoic acid methyl ester 1.4 g p-Hydroxybenzoic acid propyl ester 0.6 g

1 'PPPPRdBf @Flil EXAMPLE l3 Continued Preparation of a Syrup:

Composition:

Citric acid Sodium cyclamate Distilled water Glycerol Sodium carboxymethyl cellulose Sugar The active substance and the colloidal silicon dioxide are passed through a sieve of 1.2 mm mesh diameter (I).

The p-hydroxybenzoic acid esters, the citric acid and the sodium cyclamate are dissolved in the given amount of boiling distilled water; the glycerol is then added to this solution (II). The sodium carboxymethyl cellulose and the sugar are thoroughly mixed (III).

Composition III is then added at C to Solution II under stirring until complete dissolution of III. The viscous, slightly turbid liquid is cooled to room temperature, filtered, if necessary and mixed with composition 1. Water is added to the resulting mixture up to the prescribed weight of l.l55.0 g, and the syrup obtained is I homogenized.

What is claimed is:

(III) wherein X is halogen, and R is unsubstituted or hydroxy-substituted alkyl having from one to five carbon atoms, or carbalkoxy having from one to five carbon atoms in the alkyl moiety. 2. A compound according to claim 1, wherein X is chloro and R is ethoxycarbonyl.

3. A compound according to claim 1, wherein X is bromo and R is methyl.

4. A compound according to claim 1, wherein X is bromo and R is 2-hydroxyethyl. 

2. A compound according to claim 1, wherein X is chloro and R is ethoxycarbonyl.
 3. A compound according to claim 1, wherein X is bromo and R is methyl.
 4. A compound according to claim 1, wherein X is bromo and R is 2-hydroxyethyl. 